ANI neural network potentials for small molecule pKa prediction.

The pKa value of a molecule is of interest to chemists across a broad spectrum of fields including pharmacology, environmental chemistry and theoretical chemistry. Determination of pKa values can be accomplished through several experimental methods such as NMR techniques and titration together with computational techniques such as DFT calculations. However, all of these methods remain time consuming and computationally expensive. In this work we develop a method for the rapid calculation of pKa values of small molecules which utilises a combination of neural network potentials, low energy conformer searches and thermodynamic cycles. We show that neural network potentials trained on different phase and charge states can be employed in tandem to predict the full thermodynamic energy cycle of molecules. Focusing here on imidazolium derived carbene species, the method utilised can easily be extended to other functional groups of interest such as amines with further training.

Novel Thermoreversible Reverse-Phase-Shift Foam With Deployment System for Treatment of Penetrating Globe Trauma in a Newly Described Porcine Model.

INTRODUCTION: The initial management of penetrating ocular injuries is a major sight-threatening problem for both civilian and military medicine. A novel device (Eye-Aid) temporarily tamponades leakage from such injuries while being easy to remove upon arrival to specialized ophthalmologic care. Eye-Aid consists of a protective eye shield with an adhesive backing that connects to a portable canister containing rapidly deployable thermoresponsive foam. The aim of this study was to compare the use of the novel Eye-Aid device to control in a new live swine ocular injury model. MATERIALS AND METHODS: Bilateral penetrating ocular injuries were created on 14 male Yorkshire swine in a standardized manner using a 16-gauge needle device to puncture the central cornea and cause a full-thickness wound. Researchers randomized eye intervention side, with the contralateral eye used as paired control. Two minutes after the injury, the eye shield components of the Eye-Aid system, which has a sticky pad for attachment to the skin and a luer-lock for foam deployment, were placed bilaterally. Eight minutes after the injury, foam was deployed for the intervention eye according to the device instructions for use. For the control eye, no additional procedures were performed. Six hours post-injury, end A-scan and intraocular pressure (IOP) were measured. Primary study outcome was change in axial length of the globe. Secondary outcomes were as follows: (1) Presence of full anterior chamber collapse, defined as a lack of measurable anterior lens capsule-reflex (ALC-reflex) on A-scan and (2) change in IOP. Outcomes were analyzed as paired intra-animal data, with intervention and control data for each animal. A paired t-test was used to analyze the difference in axial length change and IOP change between treatment groups, whereas a conditional logistic regression was used to analyze dichotomous ALC-reflex outcome and estimate the odds ratio associated with the Eye-Aid device. RESULTS: A significant difference (P < .0001) in mean change in axial length between intervention (-210 µm) and control (-1,202 µm) groups was found. There was a significant difference in ALC-reflex presence, with 79% of eyes having an ALC-reflex in the intervention group, compared to 14% in the control (P = .008). IOP remained higher in the intervention group, with a mean change of -1.5 mmHg for the intervention group compared to -4.0 mmHg in the control (P = .0001). CONCLUSIONS: This study describes the first development of an in vivo large animal ocular injury model that realistically approximates the emergent time course and pathophysiology of patients with full-thickness corneal open globe injuries. It also gives the first description of using thermoreversible hydrogel foam for such injuries. Eye-Aid was found to be significantly better than control for treatment of such injuries, based on measurements of both structure and pressure. Assuming that the absence of an ALC-reflex demonstrates complete anterior chamber collapse, the Eye-Aid group demonstrated a 79% eye "save" rate compared to only 14% in the control group, as described earlier. This results in a Number Needed to Treat of 3 for this finding. Eye-Aid additionally demonstrated several characteristics that would be beneficial in a device targeted for emergent deployment by non-ophthalmologists.

CNNs trained with adult data are useful in pediatrics. A pneumonia classification example.

BACKGROUND AND OBJECTIVES: The scarcity of data for training deep learning models in pediatrics has prompted questions about the feasibility of employing CNNs trained with adult images for pediatric populations. In this work, a pneumonia classification CNN was used as an exploratory example to showcase the adaptability and efficacy of such models in pediatric healthcare settings despite the inherent data constraints. METHODS: To develop a curated training dataset with reduced biases, 46,947 chest X-ray images from various adult datasets were meticulously selected. Two preprocessing approaches were tried to assess the impact of thoracic segmentation on model attention outside the thoracic area. Evaluation of our approach was carried out on a dataset containing 5,856 chest X-rays of children from 1 to 5 years old. RESULTS: An analysis of attention maps indicated that networks trained with thorax segmentation placed less attention on regions outside the thorax, thus eliminating potential bias. The ensuing network exhibited impressive performance when evaluated on an adult dataset, achieving a pneumonia discrimination AUC of 0.95. When tested on a pediatric dataset, the pneumonia discrimination AUC reached 0.82. CONCLUSIONS: The results of this study show that adult-trained CNNs can be effectively applied to pediatric populations. This could potentially shift focus towards validating adult models over pediatric population instead of training new CNNs with limited pediatric data. To ensure the generalizability of deep learning models, it is important to implement techniques aimed at minimizing biases, such as image segmentation or low-quality image exclusion.

Good Psychiatric Management of Borderline Personality Disorder: Foundations and Future Challenges.

Borderline personality disorder is a common condition characterized by numerous comorbid conditions, frequent use of clinical services, and an elevated lifetime risk for suicide. Good psychiatric management (GPM) was developed for patients with borderline personality disorder with the purpose of supporting wider community adoption and dissemination compared with existing therapies. The authors aimed to review the foundations and development of GPM, in particular the initial Canadian study assessing the therapy. They then reviewed the progress in research arising from the initial study and explored the research and educational opportunities needed to further the development of GPM for patients with borderline personality disorder. Research has indicated that patients with borderline personality disorder with complex comorbid conditions and impulsivity may benefit from GPM. Future research needs include noninferiority and equivalence studies comparing GPM with another evidence-based treatment; studies demonstrating that evidence-based therapies for borderline personality disorder improve functioning; and research on more accessible therapies, mechanisms of action for evidence-based therapies, extending therapies to patients with borderline personality disorder and significant comorbid conditions, and modifying therapies for men with borderline personality disorder. Attention should be directed toward testing stepped care models and integrating therapies such as GPM into psychiatric training programs. GPM is in development but shows promise as a therapy that is effective and accessible and that can be widely disseminated.

Using microfluidic shear to assess transfusion requirements in trauma patients.

Background: Viscoelastic assays have widely been used for evaluating coagulopathies but lack the addition of shear stress important to in vivo clot formation. Stasys technology subjects whole blood to shear forces over factor-coated surfaces. Microclot formation is analyzed to determine clot area (CA) and platelet contractile forces (PCFs). We hypothesize the CA and PCF from this novel assay will provide information that correlates with trauma-induced coagulopathy and transfusion requirements. Methods: Blood samples were collected on adult trauma patients from a single-institution prospective cohort study of high-level activations. Patient and injury characteristics, transfusion data, and outcomes were collected. Thromboelastography, coagulation studies, and Stasys assays were run on paired samples collected at admission. Stasys CA and PCFs were quantified as area under the curve calculations and maximum values. Normal ranges for Stasys assays were determined using healthy donors. Data were compared using Kruskal-Wallis tests and simple linear regression. Results: From March 2021 to January 2023, 108 samples were obtained. Median age was 37.5 (IQR 27.5-52) years; patients were 77% male. 71% suffered blunt trauma, 26% had an Injury Severity Score of ≥25. An elevated international normalized ratio significantly correlated with decreased cumulative PCF (p=0.05), maximum PCF (p=0.05) and CA (p=0.02). Lower cumulative PCF significantly correlated with transfusion of any products at 6 and 24 hours (p=0.04 and p=0.05) as well as packed red blood cells (pRBCs) at 6 and 24 hours (p=0.04 and p=0.03). A decreased maximum PCF showed significant correlation with receiving any transfusion at 6 (p=0.04) and 24 hours (p=0.02) as well as transfusion of pRBCs, fresh frozen plasma, and platelets in the first 6 hours (p=0.03, p=0.03, p=0.03, respectively). Conclusions: Assessing coagulopathy in real time remains challenging in trauma patients. In this pilot study, we demonstrated that microfluidic approaches incorporating shear stress could predict transfusion requirements at time of admission as well as requirements in the first 24 hours. Level of evidence: Level II.

Do serial troponins predict the need for cardiac evaluation in trauma patients after ground-level fall?

Purpose: Troponin T levels are routinely checked in trauma patients after experiencing a ground-level fall to identify potential cardiac causes of syncope. An elevated initial troponin prompts serial testing until the level peaks. However, the high sensitivity of the test may lead to repeat testing that is of little clinical value. Here, we examine the role of serial troponins in predicting the need for further cardiac workup in trauma patients after sustaining a fall. Methods: Retrospective review of all adult trauma activations for ground-level fall from January 1, 2021 to December 31, 2021 in patients who were hemodynamically and neurologically normal at presentation. Outcomes evaluated included need for cardiology consult, admission to cardiology service, outpatient cardiology follow-up, cardiology intervention and in-hospital mortality. Results: There were 1555 trauma activations for ground-level fall in the study period. The cohort included 560 patients evaluated for a possible syncopal fall, hemodynamically stable, Glasgow Coma Scale score of 15, and with a troponin drawn at presentation. The initial median troponin was 20 ng/L (13-37). Second troponin values were drawn on 58% (median 33 ng/L (22-52)), with 42% of patients having an increase from first to second test. 29% of patients had a third troponin drawn (median 42 ng/L (26-67)). The initial troponin value was significantly associated with undergoing a subsequent echo (p=0.01), cardiology consult (p<0.01), admission for cardiac evaluation (p<0.01), cardiology follow-up (p<0.01), and in-hospital mortality (p=0.01); the initial troponin was not associated with cardiac intervention (p=0.91). An increase from the first to second troponin was not associated with any of outcomes of interest. Analysis was done with cut-off values of 30 ng/L, 50 ng/L, 70 ng/L, and 90 ng/L; a troponin T threshold of 19 ng/L was significant for cardiology consult (p=0.01) and cardiology follow-up (p=0.04). When the threshold was increased to 50 ng/L, it was also significant for admission for cardiac issue (p<0.01). When the threshold was increased to 90 ng/L, it was significant for the same three outcomes and in-hospital mortality (p=0.04). Conclusion: The initial serum troponin has clinical value in identifying underlying cardiac disease in patients who present after ground-level fall; however, that serial testing is likely of little value. Further, using a cut-off of >50 ng/L as a threshold for further clinical evaluation would improve the utility of the test and likely reduce unnecessary hospital stays and costs for otherwise healthy patients. Level of evidence: Level III.

Does the setting for intradetrusor onabotulinumtoxinA injection for management of overactive bladder matter?

Introduction: Intradetrusor onabotulinumtoxinA (Botox) injections, to treat idiopathic overactive bladder (OAB), can be performed in the office setting under local analgesia alone or in the operating room (OR) under local and/or sedation. The objective of this study was to compare the symptomatic improvement in patients with OAB who underwent treatment with intradetrusor onabotulinumtoxinA injections in an in-office versus the OR setting. Methods: We performed a multicenter retrospective cohort study of women with the diagnosis of refractory non-neurogenic OAB who elected to undergo treatment with intradetrusor onabotulinumtoxinA injections between January 2015 and December 2020. The electronic medical records were queried for all the demographic and peri-procedural data, including the report of subjective improvement post procedure. Patients were categorized as either "in-office" versus "OR" based on the setting in which they underwent their procedure. Results: Five hundred and thirty-nine patients met the inclusion criteria: 297 (55%) in the in-office group and 242 (45%) in the OR group. A total of 30 (5.6%) patients reported retention after their procedure and it was more common in the in-office group (8.1%) versus the OR group (2.5%), (P = 0.003). The rate of urinary tract infection within 6 months of the procedure was higher in the OR group (26.0% vs. 16.8%, P = 0.009). The overall subjective improvement rate was 77% (95% confidence interval: 73%-80%). Patients in the OR group had a higher reported improvement as compared to the in-office group (81.4% vs. 73.3%, P = 0.03). Conclusions: In this cohort study of patients with OAB undergoing intradetrusor onabotulinumtoxinA injections, post procedural subjective improvement was high regardless of the setting in which the procedure was performed.

Differences in Perceived Stress During the COVID-19 Pandemic Among Military Dental Postgraduate Residents.

INTRODUCTION: In military training settings, stress can improve focus and motivation fostering effective learning. However, high perceived stress can be debilitating resulting in poor learning and clinical errors. Multiple studies have focused on medical residency stress; but there has been minimal focus on dental residents and even less on the impact of the unique stressors from the COVID-19 pandemic. The objectives of this study were to determine the impact of the COVID-19 pandemic on perceived stress of residents in a military dental residency training program and explore the association among perceived stress and anxiety, depression, sleep quality, and social support. MATERIALS AND METHODS: Dental residents (N = 20) at the Naval Postgraduate Dental School participated in this study. Residents were assessed via self-report measures quarterly from March 2020 through June 2021. The assessment included measures of anxiety (GAD-7), depression (PHQ-9), perceived stress (PSS), fatigue (FSI), and social support (DUKE-SSQ). RESULTS: Before the pandemic shutdown, 60% of participants reported high perceived stress. These residents reported an initial decrease in symptoms of anxiety, depression, and fatigue compared to residents reporting low pre-pandemic perceived stress but returned to baseline levels post-shutdown. Additionally, the high stress participants reported lower social support. CONCLUSIONS: Based on pre-pandemic perceived stress, participants responded differently to the impact of the pandemic shutdown. The low baseline stress participants may have a more robust sense of grit and resilience. These findings suggest that postgraduate dental training programs should integrate coping skills training opportunities, especially for residents reporting high perceived stress before residency.

Dynamical and individualised approach of transcranial ultrasound neuromodulation effects in non-human primates.

Low-frequency transcranial ultrasound stimulation (TUS) allows to alter brain functioning with a high spatial resolution and to reach deep targets. However, the time-course of TUS effects remains largely unknown. We applied TUS on three brain targets for three different monkeys: the anterior medial prefrontal cortex, the supplementary motor area and the perigenual anterior cingulate cortex. For each, one resting-state fMRI was acquired between 30 and 150 min after TUS as well as one without stimulation (control). We captured seed-based brain connectivity changes dynamically and on an individual basis. We also assessed between individuals and between targets homogeneity and brain features that predicted TUS changes. We found that TUS prompts heterogenous functional connectivity alterations yet retain certain consistent changes; we identified 6 time-courses of changes including transient and long duration alterations; with a notable degree of accuracy we found that brain alterations could partially be predicted. Altogether, our results highlight that TUS induces heterogeneous functional connectivity alterations. On a more technical point, we also emphasize the need to consider brain changes over-time rather than just observed during a snapshot; to consider inter-individual variability since changes could be highly different from one individual to another.

A novel, reverse-phase-shifting, thermoreversible foaming hydrogel containing antibiotics for the treatment of thermal burns in a swine model - A pilot study.

BACKGROUND: This study compared a novel topical hydrogel burn dressing (CI-PRJ012) to standard of care (silver sulfadiazine) and to untreated control in a swine thermal burn model, to assess for wound healing properties both in the presence and absence of concomitant bacterial inoculation. METHODS: Eight equal burn wounds were created on six Yorkshire swine. Half the wounds were randomized to post-burn bacterial inoculation. Wounds were subsequently randomized to three treatments groups: no intervention, CI-PRJ012, or silver sulfadiazine cream. At study end, a blinded pathologist evaluated wounds for necrosis and bacterial colonization. RESULTS: When comparing CI-PRJ012 and silver sulfadiazine cream to no treatment, both agents significantly reduced the amount of necrosis and bacteria at 7 days after wound creation (p < 0.01, independently for both). Further, CI-PRJ012 was found to be significantly better than silver sulfadiazine (p < 0.02) in reducing bacterial colonization. For wound necrosis, no significant difference was found between silver sulfadiazine cream and CI-PRJ012 (p = 0.33). CONCLUSIONS: CI-PRJ012 decreases necrosis and bacterial colonization compared to no treatment in a swine model. CI-PRJ012 appeared to perform comparably to silver sulfadiazine. CI-PRJ012, which is easily removed with the application of room-temperature water, may provide clinical advantages over silver sulfadiazine.

Sortase-Modified Cholera Toxoids Show Specific Golgi Localization.

Cholera toxoid is an established tool for use in cellular tracing in neuroscience and cell biology. We use a sortase labeling approach to generate site-specific N-terminally modified variants of both the A2-B5 heterohexamer and B5 pentamer forms of the toxoid. Both forms of the toxoid are endocytosed by GM1-positive mammalian cells, and while the heterohexameric toxoid was principally localized in the ER, the B5 pentamer showed an unexpectedly specific localization in the medial/trans-Golgi. This study suggests a future role for specifically labeled cholera toxoids in live-cell imaging beyond their current applications in neuronal tracing and labeling of lipid rafts in fixed cells.

Cost-Effective, Implant-Free, All-Suture Modified Subpectoral Biceps Tenodesis Technique.

Tendinopathy and partial tears of the long head of the biceps tendon are a common cause of anterior shoulder pain and are often associated with many other shoulder pathologies. Multiple open and arthroscopic tenodesis techniques exist in the literature, with varying locations along the proximal humerus and a multitude of different implants. This article describes a cost-effective, implant-free, subpectoral biceps tenodesis technique that can be used as open or in conjunction with arthroscopy. Our technique differs from other tunnel techniques in its modified docking configuration into the intraosseous canal, decreasing stresses at the bone-tendon interface. With the cost amounting to 5% to 10% of techniques using implants, this is a cost-saving and reliable option for tenodesis.

Pelvic Floor Dysfunction Among Persons With Marfan and Loeys-Dietz Syndrome.

IMPORTANCE: Connective tissue disorders are proposed in the literature to be predisposing risk factors for pelvic floor disorders. Prior data characterizing the prevalence of and symptom burden related to pelvic floor disorders are limited for individuals with Marfan syndrome and are nonexistent for those with Loeys-Dietz syndrome. OBJECTIVE: The objective of this study was to determine the prevalence and severity of symptoms related to pelvic floor disorders among individuals with Marfan syndrome and Loeys-Dietz syndrome using the Pelvic Floor Distress Inventory-20 (PFDI-20). STUDY DESIGN: In this cross-sectional study, a survey including the PFDI-20 was administered to biologically female individuals older than 18 years with a confirmed diagnosis of Marfan syndrome or Loeys-Dietz Syndrome. Respondents were solicited through the websites, email lists, and social media forums of The Marfan Foundation and The Loeys-Dietz syndrome Foundation. RESULTS: A total of 286 respondents were included in the final analysis, 213 with Marfan syndrome and 73 with Loeys-Dietz syndrome. The median PFDI-20 score of the cohort was 43.8. Individuals with Loeys-Dietz syndrome had higher PFDI-20 scores and were more likely to have established risk factors for pelvic floor disorders that correlated with their PFDI-20 scores compared with those with Marfan syndrome. CONCLUSIONS: Respondents with Marfan syndrome and Loeys-Dietz syndrome experience a high burden of symptoms related to pelvic floor disorders. Despite the similar pathophysiology and clinical manifestations of these disorders, there were differences in PFDI-20 responses that may suggest that these diseases differ in the ways they affect the pelvic floor.

The Mutagenic Plasticity of the Cholera Toxin B-Subunit Surface Residues: Stability and Affinity.

Mastering selective molecule trafficking across human cell membranes poses a formidable challenge in healthcare biotechnology while offering the prospect of breakthroughs in drug delivery, gene therapy, and diagnostic imaging. The cholera toxin B-subunit (CTB) has the potential to be a useful cargo transporter for these applications. CTB is a robust protein that is amenable to reengineering for diverse applications; however, protein redesign has mostly focused on modifications of the N- and C-termini of the protein. Exploiting the full power of rational redesign requires a detailed understanding of the contributions of the surface residues to protein stability and binding activity. Here, we employed Rosetta-based computational saturation scans on 58 surface residues of CTB, including the GM1 binding site, to analyze both ligand-bound and ligand-free structures to decipher mutational effects on protein stability and GM1 affinity. Complimentary experimental results from differential scanning fluorimetry and isothermal titration calorimetry provided melting temperatures and GM1 binding affinities for 40 alanine mutants among these positions. The results showed that CTB can accommodate diverse mutations while maintaining its stability and ligand binding affinity. These mutations could potentially allow modification of the oligosaccharide binding specificity to change its cellular targeting, alter the B-subunit intracellular routing, or impact its shelf-life and in vivo half-life through changes to protein stability. We anticipate that the mutational space maps presented here will serve as a cornerstone for future CTB redesigns, paving the way for the development of innovative biotechnological tools.

Development of the multivariate administrative data cystectomy model and its impact on misclassification bias.

BACKGROUND: Misclassification bias (MB) is the deviation of measured from true values due to incorrect case assignment. This study compared MB when cystectomy status was determined using administrative database codes vs. predicted cystectomy probability. METHODS: We identified every primary cystectomy-diversion type at a single hospital 2009-2019. We linked to claims data to measure true association of cystectomy with 30 patient and hospitalization factors. Associations were also measured when cystectomy status was assigned using billing codes and by cystectomy probability from multivariate logistic regression model with covariates from administrative data. MB was the difference between measured and true associations. RESULTS: 500 people underwent cystectomy (0.12% of 428 677 hospitalizations). Sensitivity and positive predictive values for cystectomy codes were 97.1% and 58.6% for incontinent diversions and 100.0% and 48.4% for continent diversions, respectively. The model accurately predicted cystectomy-incontinent diversion (c-statistic [C] 0.999, Integrated Calibration Index [ICI] 0.000) and cystectomy-continent diversion (C:1.000, ICI 0.000) probabilities. MB was significantly lower when model-based predictions was used to impute cystectomy-diversion type status using for both incontinent cystectomy (F = 12.75; p < .0001) and continent cystectomy (F = 11.25; p < .0001). CONCLUSIONS: A model using administrative data accurately returned the probability that cystectomy by diversion type occurred during a hospitalization. Using this model to impute cystectomy status minimized MB. Accuracy of administrative database research can be increased by using probabilistic imputation to determine case status instead of individual codes.

A Novel Peritoneal Packing Method for Management of Hyperkalemia During Acute Kidney Injury in Trauma.

INTRODUCTION: United States Military operations in resource limited areas are increasing. Furthermore, future peer or near-peer conflicts will require caring for larger numbers of casualties with limited resources. In this setting, traditional renal replacement therapy is not feasible and novel methods are required to address severe acute kidney injury in austere environments lacking definitive therapies. Here, we describe experiments designed to determine the efficacy of a novel peritoneal packing material (Potassium Binding Pack-PBP, CytoSorbents INC) for the acute management of severe hyperkalemia. MATERIALS AND METHODS: Male swine (52 ±1 kg) were nephrectomized via midline laparotomy under a plane of anesthesia and randomized into one of two experimental groups (PBP & CON). Exogenous potassium was infused to achieve a serum potassium level of 7.5 mEq/L. Novel potassium absorbing packs (PBP) or sham packs (CON) were placed in the right and left upper quadrants, and the right and left paracolic gutters of the abdomen to simulate four-quadrant packing (n = 6, n = 5, respectively). Two liters of peritoneal dialysis fluid was instilled into the abdomen and temporary closure performed. Animals were observed for 12 hours. Serum and peritoneal fluid (dialysate) potassium levels were sampled at T = 15, 30, 60 min, and Q60min thereafter. Animals were humanely euthanized at the end of the observation period. RESULTS: Baseline characteristics were similar between groups. Pairwise analysis showed that serum potassium concentrations were significantly lower in the PBP group compared to CON at T = 540 and T = 720 (P = 0.006 and P = 0.015, respectively). Potassium concentrations were significantly lower in dialysate of the PBP group compared to CON at all time points after T = 15 (T = 30, P = 0.017; T = 60 through T = 720, P < 0.001). CONCLUSIONS: This is the first demonstration of an effective technology for the management of hyperkalemia in trauma in the absence of standard of care; renal replacement therapy. We identified that PBP was able to consistently maintain a concentration gradient between dialysate in the peritoneum and system potassium concentration throughout the experiment. Furthermore, systemic potassium concentrations were reduced in a clinically relevant manner in the PBP group compared to CON. This suggests that peritoneal packing technology for the management of metabolic disturbances in trauma has potential for clinical application. These results are preliminary and should be interpreted with caution.

Cell-Free Hemoglobin in the Pathophysiology of Trauma: A Scoping Review.

OBJECTIVES: Cell-free hemoglobin (CFH) is a potent mediator of endothelial dysfunction, organ injury, coagulopathy, and immunomodulation in hemolysis. These mechanisms have been demonstrated in patients with sepsis, hemoglobinopathies, and those receiving transfusions. However, less is known about the role of CFH in the pathophysiology of trauma, despite the release of equivalent levels of free hemoglobin. DATA SOURCES: Ovid MEDLINE, Embase, Web of Science Core Collection, and BIOSIS Previews were searched up to January 21, 2023, using key terms related to free hemoglobin and trauma. DATA EXTRACTION: Two independent reviewers selected studies focused on hemolysis in trauma patients, hemoglobin breakdown products, hemoglobin-mediated injury in trauma, transfusion, sepsis, or therapeutics. DATA SYNTHESIS: Data from the selected studies and their references were synthesized into a narrative review. CONCLUSIONS: Free hemoglobin likely plays a role in endothelial dysfunction, organ injury, coagulopathy, and immune dysfunction in polytrauma. This is a compelling area of investigation as multiple existing therapeutics effectively block these pathways.

Clinical relevance of lung function trajectory clusters in middle-aged and older adults.

Background: The determinants and health outcomes of lung function trajectories in adults among the general population are poorly understood. We aimed to identify and characterise clusters of lung function trajectories in adults aged ≥45 years. Methods: Gaussian finite-mixture modelling was applied to baseline and annualised change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio z-scores in participants of the Rotterdam Study, a prospective population-based cohort study, with repeated spirometry (n=3884; mean±sd age 64.7±8.9 years). Longitudinal outcomes were all-cause mortality, respiratory outcomes (symptoms, COPD (FEV1/FVC <0.7 in absence of asthma), preserved ratio impaired spirometry (PRISm; FEV1/FVC ≥0.7 and FEV1 or FVC <80%)), smoking cessation and weight changes. Independent risk factors, including genetics, were identified by multiple logistic regression. Results: We identified eight trajectory clusters, with the reference group having persistently normal spirometry (prevalence 42.8%). Three clusters showed higher mortality, adjusted for confounders: 1) the persistently low FEV1 cluster (prevalence 6.8%, hazard ratio (HR) 1.71, 95% CI 1.37-2.13); 2) rapid FEV1 decliners (prevalence 4.6%, HR 1.48, 95% CI 1.10-1.99); and 3) FVC decliners (prevalence 3.7%, HR 1.49, 95% CI 1.09-2.03). In contrast, FVC improvers (prevalence 6.7%, HR 0.61, 95% CI 0.41-0.90) and persistently high FEV1 (prevalence 29.2%, HR 0.82, 95% CI 0.69-0.98) were protective trajectory clusters. Clusters were characterised by differences in genetic predisposition (polygenic scores of FEV1 and FEV1/FVC), demographics, cigarette smoking, respiratory symptoms (chronic cough, wheezing and dyspnoea), cardiovascular factors (body mass index, hypertension and heart failure) and serum C-reactive protein levels. Frailty, weight changes and the development of respiratory symptoms, COPD and PRISm were significantly associated with trajectory clusters. Conclusions: This study reveals clinically relevant lung function trajectory clusters in older adults of the general population.

Early generation of a precursor CD8 T cell that can adapt to acute or chronic viral infection.

Virus specific PD-1+ TCF-1+ TOX+ stem-like CD8+ T cells are essential for maintaining T cell responses during chronic infection and are also critical for PD-1 directed immunotherapy. In this study we have used the mouse model of chronic LCMV infection to examine when these virus specific stem-like CD8+ T cells are generated during the course of chronic infection and what is the role of antigen in maintaining the stem-like program. We found that these stem-like CD8+ T cells are generated early (day 5) during chronic infection and that antigen is essential for maintaining their stem-like program. This early generation of stem-like CD8+ T cells suggested that the fate commitment to this cell population was agnostic to the eventual outcome of infection and the immune system prepares a priori for a potential chronic infection. Indeed, we found that an identical virus specific stem-cell like CD8+ T cell population was also generated during acute LCMV infection but these cells were lost once the virus was cleared. To determine the fate of these early PD-1+TCF-1+TOX+ stem-like CD8+ T cells that are generated during both acute and chronic LCMV infection we set up two reciprocal adoptive transfer experiments. In the first experiment we transferred day 5 stem-like CD8+ T cells from chronically infected into acutely infected mice and examined their differentiation after viral clearance. We found that these early stem-like CD8+ T cells downregulated canonical markers of the chronic stem-like CD8+ T cells and expressed markers (CD127 and CD62L) associated with central memory CD8+ T cells. In the second experiment, we transferred day 5 stem-like cells from acutely infected mice into chronically infected mice and found that these CD8+ T cells could function like resource cells after transfer into a chronic environment by generating effector CD8+ T cells in both lymphoid and non-lymphoid tissues while also maintaining the number of stem-like CD8+ T cells. These findings provide insight into the generation and maintenance of virus specific stem-like CD8+ T cells that play a critical role in chronic viral infection. In particular, our study highlights the early generation of stem-like CD8+ T cells and their ability to adapt to either an acute or chronic infection. These findings are of broad significance since these novel stem-like CD8+ T cells play an important role in not only viral infections but also in cancer and autoimmunity.